Ritodrine-induced rhabdomyolysis and psychiatric symptoms: a case report and literature review

Background Ritodrine hydrochloride, a β2-adrenergic agonist, has been widely used in Asia and Europe to treat preterm labor in pregnant women. It has some typical side effects, such as palpitations, pulmonary edema, and hypokalemia. Here, we report a case of rhabdomyolysis and psychiatric symptoms might be associated with intravenous ritodrine. Case presentation A 32-year-old Chinese primigravida woman who was pregnant with twins by in vitro fertilization-embryo transfer was diagnosed with placenta previa and threatened abortion at 21 gestational weeks (GW). The patient was then treated with ritodrine hydrochloride. The initial dose of ritodrine was 150 μg/min, gradually increasing to 360 μg/min at 235/7 GW and 400 μg/min at 271/7 GW. Magnesium sulfate was added to the ritodrine regimen at 215/7 GW in dosage of 1-2 g/h. Psychiatric symptoms appeared at 245/7, 265/7, and 273/7 GW, manifesting as depression, anxiety, and suicidal tendencies. Severe muscle pain in her limbs and general weakness appeared after six weeks of ritodrine administration, which might have been a sign of rhabdomyolysis resulting from ritodrine administration. After ceasing the administration of ritodrine, the muscle pain and relevant data from laboratory tests on the patient were significantly improved, and her mood was stable. It is worth noting that this is the first time to report psychiatric symptoms may associated with the administration of ritodrine. In addition, we reviewed and analyzed six reported cases of rhabdomyolysis caused by ritodrine. Conclusion Our results suggest that we should pay more attention to the risk of rhabdomyolysis and psychiatric symptoms induced by intravenous ritodrine hydrochloride, especially in patients with a history of neuromuscular disorder, or concomitant use of magnesium sulfate.


Background
The use of β2-adrenergic agonists, such as ritodrine hydrochloride, is common for preventing preterm birth worldwide [1]. Ritodrine is the only agent approved by the US Food and Drug Administration (FDA) for reducing preterm birth within 48 hours of initiation of treatment [2]. In 2012, the American College of Gynecologists (ACOG) recommended β-adrenergic agonists as the first-line tocolytic treatment [3]. However, its use has decreased in some developed countries due to its various side effects, including palpitations, pulmonary edema, hypokalemia, and granulocytopenia [2,4]. The FDA and the European Medicines Agency (EMA) have recommended discontinuation of oral administration of ritodrine [5]. since the most important objective of tocolysis is to gain time for antenatal corticosteroids to become effective [6]. Moreover, tocolytic agents may be associated with an increased risk of chorioamnionitis [7], and the cardiovascular risk is raised when ritodrine is used for a prolonged period (more than 48 hours) [8]. The product information of ritodrine recommend that longterm (more than 48 hours) ritodrine treatment should closely monitor the risk of cardiovascular-related adverse reactions in pregnant women and fetuses. However, in some other countries, such as China, Japan, and Korea, ritodrine is still used as the first-line tocolytic treatment and is used for a long duration [9,10].
Here, we report a pregnant woman with twins after being treated with ritodrine for tocolysis for three weeks, who developed psychiatric symptoms manifesting as depression, anxiety, and suicidal tendencies. In addition, she developed rhabdomyolysis after administration of ritodrine for six weeks. It is worth noting that this is the first time to report psychiatric symptoms may associated with the administration of ritodrine. We also review and analyze the reported cases of rhabdomyolysis caused by ritodrine.

Case presentation
The patient was a 32-year-old Chinese primigravida woman who was pregnant with twins by in vitro fertilization-embryo transfer (IVF-ET). She had no history of neuromuscular disease and was hospitalized three times due to vaginal bleeding from 15 1/7 GW to 20 6/7 GW. The agents used during hospitalization were unknown. She was then transferred to The Second Xiangya Hospital of Central South University due to placenta previa and vaginal bleeding at 21 GW. On admission, ritodrine was given by IV for tocolysis. The initial dose of ritodrine was 150 μg/min, gradually increasing to 360 μg/min at 23 5/7 GW and 400 μg/min at 27 1/7 GW. Since ritodrine alone could not effectively inhibit contractions, at 21 5/7 GW, magnesium sulfate (MgSO 4 ) was used in combination with the ritodrine regimen to inhibit contractions. Two 12-mg doses of betamethasone were given intramuscularly 24 hours apart at 26 1/7 GW to accelerate fetal lung maturation. The patient experienced mood swings at 24 5/7 GW. She felt upset, had an emotional breakdown, and showed suicidal tendencies. She developed anxiety due to poor sleep at 26 5/7 GW.
At 27 3/7 GW, she had slept poorly at night and was depressed. She complained of severe muscle pain in the upper and lower limbs and general weakness, accompanied by an abnormal blood myoglobin value of 97.4 μg/L (normal, ≤70 μg/L) and a serum high-sensitivity troponin value of 21.4 pg/mL (normal, 0-14 pg/mL). Her alanine transaminase (ALT) value of 50.8 U/L (normal 7-40 U/L) also began to increase. Her blood creatine kinase (CK) value of 103 U/L (normal, 40-200 U/L) was normal, and Aspartate transaminase (AST) value of 25.6 U/L (normal, 13-35 U/L) was normal. We speculate that rhabdomyolysis had resulted from ritodrine and stopped ritodrine use immediately at 9:00 a.m., while MgSO 4 at a dose of 1-2 g/h was still used. At 5:00 p.m., the patient stated that the muscle pain was significantly improved, and the mood became stable.
At 27 4/7 GW, because of severe abdominal pain and uterine dilatation, she delivered two babies. The first female infant weighed 880 g, with an Apgar score of 3/6/7 (1/5/10 minutes), was admitted to the neonatal intensive care unit. The second male infant was delivered by breech extraction and weighed 1080 g, with an Apgar score of 2/2/2 (1/5/10 minutes), did not breathe spontaneously and did not respond to external stimuli. His parents then decided to give up on further rescue. The patient complained of grief during the first day after delivery, and her mood was stable. The serum high-sensitivity troponin T value of ≤8 pg/mL (normal, ≤15.91 pg/mL) and the ALT value of 34.4 U/L (normal, 7-40 U/L) were normal after 2 days postpartum. She was discharged 5 days after delivery, and her postpartum mood was stable. The patient was satisfied with the treatment she received.

Ritodrine-induced rhabdomyolysis
Rhabdomyolysis is a clinical syndrome characterized by skeletal muscle destruction and the release of intracellular muscle content, which can cause systemic complications. The syndrome leads to muscle pain, weakness, dark tea-colored urine, and a significant elevation of serum CK levels. There is no universal definition of rhabdomyolysis, although the common definition includes up-regulated CK levels of more than five times the normal value [11]. In this case, we thought there were three reasons why the patient's rhabdomyolysis was probably induced by the administration of ritodrine. First, after administration of ritodrine for six weeks, the patient showed symptoms of muscle pain and generalized weakness, and the blood myoglobin, troponin, and ALT values increased. Second, the product information points out that ritodrine has an adverse reaction of rhabdomyolysis. Third, and most importantly, the muscle pain and general weakness were significantly relieved when the patient stopped administration of ritodrine for eight hours. The twins were delivered on the second day after stopping ritodrine. The serum high-sensitivity troponin T value and ALT value was normal after 2 days of postpartum. Due to the timely detection and treatment of this case, no further physical injury occurred. CK is the most sensitive test for indicating damage to muscle cells. Generally, CK increases within 12 hours after muscle damage, reaches a peak after 1-3 days, and begins to decline after 3-5 days [12]. The CK values of this patient did not increase. The possible reason was that the test time was at an early stage, so muscle damage had just occurred, and the serum CK had not yet begun to increase. We tested the CK level when muscle pain appeared in the patient, and it was normal. After that, ritodrine administration was ceased immediately, and no retest was performed after ritodrine was stopped. Therefore, we could not know whether the CK value would have subsequently increased.
In recent years, there have been some reports about the association between rhabdomyolysis and the administration of ritodrine. We searched in the databases of Pub-Med, Embase, Web of Science, and SinoMed (Chinese biomedical literature service system) using the string "ritodrine AND (rhabdomyolysis OR myalgia OR myodynia OR myosalgia)" as the search strategy from inception to January 2022. After excluding duplicate articles, conference abstracts, and articles in languages other than English and Chinese, six case reports were included in our research [12][13][14][15][16][17]. The characteristics of these six cases are shown in Table 1.
In the cases reported by Nasu et al. [14] and Ogoyama et al. [17], two pregnant women were previously diagnosed with maternal congenital myotonic dystrophy and atypical polymyositis, respectively, because of which rhabdomyolysis occurred relatively early in these women after ritodrine treatment. Nasu et al. [14] also reported a pregnant woman who received only oral ritodrine hydrochloride at a dose of 15 mg/day. Three days after administration, serum CK levels were markedly elevated and myoglobinuria was detected. Ogoyama et al. [17] reported a pregnant woman who was administered IV ritodrine at a low dosage of 67 μg/min. After three hours of ritodrine administration, severe muscle pain developed and CK levels were elevated with myoglobinuria. These cases suggest that patients with a history of neuromuscular disorders are prone to rhabdomyolysis adverse reactions when using ritodrine, and the occurrence time is relatively early and progresses relatively quickly. Ogoyama et al. [17] also found that among most patients with myotonic dystrophy, ritodrine-induced rhabdomyolysis occurred within a few hours to one day after commencing IV ritodrine, whereas in patients without myotonic dystrophy, rhabdomyolysis occurred after several days or weeks. The patient we reported here had no history of neuromuscular disorder, and the appearance of symptoms of muscle pain and general weakness occurred six weeks after the administration of ritodrine.
A retrospective cohort study [18] found that in Japan, the proportion of patients who underwent ritodrine treatment for ≥28 days was 28.7%, with only 17.2% receiving treatment for ≤48 hours.The proportional occurrence of maternal adverse effects was significantly higher for women who underwent ritodrine treatment for ≥28 days than ≤48 hours, especially in thromboembolism and gestational diabetes mellitus. The incidence of rhabdomyolysis was 3.8% among the women who underwent tocolytic treatment for ≥28 days, and 8.7% among the women who underwent tocolytic treatmen ≤48. The product information of ritodrine recommend that longterm (more than 48 hours) ritodrine treatment should closely monitor the risk of cardiovascular-related adverse reactions in pregnant women and fetuses. The guidelines [3] recommend that tocolytic treatment should be limited to 48 hours due to the risk of risk of cardiovascular. However, in clinical practice, long-term tocolysis above 48 hours is common in both China and Japan [10,18]. This prompts us to focus on the risk of adverse drug reactions in patients with long-term ritodrine use.
It is worth mentioning that the woman in our reported case had concomitant use of MgSO 4 . Hypermagnesemia can lead to neuromuscular toxicity, severe hypermagnesemia can result in loss of deep tendon reflexes and muscle paralysis. The plasma Mg concentration of the pregnant woman in this case was normal during hospitalization. Matsuda et al. [19] performed a retrospective cohort study to evaluate the relationship between tocolytic therapy and CK levels. They found that the total doses of ritodrine and MgSO 4 in the abnormal CK group were significantly higher than in the normal CK group. Furthermore, 100% of the abnormal CK group had concomitant use of MgSO 4 , while 50% of the normal CK group had concomitant use of MgSO 4 . However, this study did not compare the changes in CK levels between ritodrine use alone and ritodrine combined with MgSO 4 . Yada et al. [10] found that the use of ritodrine in combination with MgSO 4 was associated with the occurrence of critical neonatal hyperkalemia in late preterm infants. Therefore, in pregnant women who use ritodrine and concomitant MgSO 4 , we should pay close attention to the risk of adverse reactions in mothers and newborns.

Ritodrine-induced psychiatric symptoms
Ritodrine can cause adverse reactions in the central nervous system, including dizziness, lethargy, headache, and tremors [9], but there were no previous reports of psychiatric symptoms. To the best of our knowledge, this is the first case reporting that IV ritodrine probably associated with psychiatric symptoms. We analyzed all the medications that were administered during the patient's hospitalization, GW.
Severe muscle pain in the limbs appeared after ritodrine administration 3 hours.
Local pain appeared after 9 hours of treatment as long as the front thigh bended, which would disappeared as long as straightening.
One hour later, emergency cesarean section was performed due to fetal distress. The muscle pain of lower limbs increased after cesarean section. The urine was slightly darker and yellow. Sun  including MgSO 4 , cefoxitin, progesterone, dydrogesterone, potassium chloride, and iron polysaccharide complex capsules. None of these agents was considered capable of inducing the occurrence of psychiatric symptoms. Liu et al. [20] performed a 14-year retrospective study and found that ritodrine treatment for preterm labor was a significant risk factor for postpartum depression, especially in the form of an injection. This study lets us link the psychiatric symptoms of the patient in the present study with ritodrine. According to the patient's self-report, she had no history of psychiatric disorders but used to be rebellious in adolescence and even had suicidal tendencies once. However, she did not seek medical treatment at that time and had shown great emotional stability over the years. The patient was admitted at 21 GW and began IV ritodrine. Psychiatric symptoms appeared at 24 5/7 GW, 26 5/7 GW, and 27 3/7 GW, manifesting as depression, anxiety, and suicidal tendencies. The patient complained of severe muscle pain in the upper and lower limbs at 27 3/7 GW. We immediately ceased administration of ritodrine at 9:00 a.m. The elimination half-life of ritodrine is 1.7-2.6 hours. The drug is eliminated after five half-lives (8.5-13 hours). The patient's psychiatric symptoms significantly improved, and her mental state was relatively stable 8 hours after drug withdrawal. At follow-up after discharge, the patient complained of worrying about her daughter, but she was in a stable mood. Therefore, we speculate that the psychiatric symptoms of this patient during pregnancy may be caused by ritodrine. In summary, we report a case of a woman pregnant with twins who developed rhabdomyolysis and psychiatric symptoms after IV ritodrine hydrochloride. We should be alert to the risk of rhabdomyolysis in patients who use ritodrine for tocolytic treatment, especially in patients with a history of neuromuscular disorder, or concomitant use of MgSO 4 . For pregnant women might have high risk factor of rhabdomyolysis used ritodrine, we should monitor the serum CK levels, urine color, and the appearance of muscle pain. If there are any abnormality, the ritodrine should be ceased and evaluated. Since the association between psychiatric symptoms and ritodrine was first reported by us, further cohort studies with large sample are needed to confirm whether IV ritodrine could induce psychiatric symptoms, and whether the psychiatric symptoms are related to the dosage and duration of ritodrine. Pregnant women at risk for psychiatric disorders who use ritodrine should be regularly monitored with self-rating scale to reduce the risk of developing psychiatric disorders.